Neuroendocrine or immune events occurring within the perinatal environment often produce effects on brain and behavior that endure throughout an organism's life span. An estimated 1/3 of pregnancies suffer complications involving infection or trauma of the uterus, fetus, or newborn, and one of the most common consequences of infection or inflammation during the perinatal period is cognitive dysfunction, including learning, memory, and attention disorders. Systemic infection with bacteria (Escherichia coli) on postnatal day 4 in rats is associated with dramatic memory impairments in conjunction with a peripheral immune challenge (lipopolysaccharide;LPS) in adulthood. The current proposal is designed to address two related questions: (1) What changes occur in the neonatal brain in response to the infection that render the brain vulnerable to a later challenge? and (2) What changes occur in the brains of neonatally-infected adult rats in response to the LPS challenge, which produce the memory impairments? The proposed experiments will test the hypothesis that long-term changes in brain microglia, the primary immune cells of the brain, occur in response to infection early in life, which then contribute to altered brain function (e.g., cytokine production, neurogenesis) and memory impairment in adulthood. This hypothesis will be tested by examining the following questions, using gene expression, protein expression, and behavioral techniques: (1) Does neonatal E. coli infection result in increased microglial reactivity in adulthood? (2) Do neonatal E. coli infection-induced changes in microglia underlie exaggerated brain cytokine responses and memory impairments in adulthood? and (3) Why does postnatal day 4 appear to be during a sensitive period for neonatal infection- induced vulnerabilities later in life? These collective data will provide novel insight into the influence of early immune activation on neural and immune system development, the role that the brain's immune response plays in cognition, and ultimate treatment decisions. PUBLIC HEALTH RELEVANCE: An estimated 1/3 of pregnancies suffer complications involving infection or trauma of the uterus, fetus, or newborn, and one of the most common consequences of infection or inflammation during the perinatal period is cognitive dysfunction, including learning, memory, and attention disorders. The data collected from this proposal will provide novel insight into the influence of early immune activation on neural and immune system development, the role that the brain's immune response plays in cognition, and ultimately treatment decisions aimed at preventing the negative consequences of early infection or trauma.